Alcohol and tissue injury from mechanisms to treatments

 描述（由申请人提供）：酒精滥用是全球发病率和死亡率的主要原因，最近的数据表明，酒精性肝病影响超过1000万美国人。除了经典的酒精使用对肝脏的影响外， 其他器官，如肠、骨骼肌、肾、脂肪组织和神经系统，也会造成与长期酗酒有关的发病率和死亡率。了解乙醇损害细胞和器官功能的常见和组织特异性机制，将导致合理设计的治疗干预措施的发展，以预防和逆转长期饮酒引起的组织损伤和疾病。东北俄亥俄州酒精中心（NOAC）的总体目标是确定乙醇诱导损伤的特定分子靶点，以及了解细胞和系统对该损伤的复杂适应性和适应不良反应，这些信息将使我们能够1）靶向治疗干预，这将减缓和/或逆转酒精诱导的器官损伤的进展，2）开发可以评估新治疗策略在相关临床人群中的疗效的特异性测定。NOAC汇集了一支优秀的跨学科研究团队，并得到了行政核心，动物模型和细胞分离核心，临床核心和试点项目核心的支持，以及俄亥俄州东北部4个主要研究机构的最先进设施：克利夫兰诊所，凯斯西储大学/大学医院，东北俄亥俄州医科大学和俄亥俄州州立大学的全国儿童医院。研究内容包括四个部分：RC 1（Brown）研究乙醇与肠道微生物代谢产物之间的相互作用以及乙醇诱导的组织损伤的产生; RC 2（You）研究肝脏中乙醇代谢对肝细胞脂质稳态的关键调节因子lipin-1和SIRT 1的影响; RC3（Dasarathy）旨在了解慢性乙醇对骨骼肌萎缩的影响，酒精性肝病和RC 4（Nagy）的关键共病特征研究了炎症和肝细胞死亡之间通过坏死性凋亡/细胞凋亡的相互作用。NOAC的长期目标是将关于乙醇破坏细胞和器官功能的特定机制的新发现转化为酒精性组织损伤患者的有效治疗策略。我们优秀的研究团队和优秀的核心设施将继续合作，以解决酒精诱导的组织损伤的关键机制和翻译问题，为将新发现转化为治疗策略的发展提供独特的优势，即乙醇作用和疾病进展的分子和细胞机制。

 DESCRIPTION (provided by applicant): Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. In addition to the classically appreciated impact of alcohol use on the liver, injury to other organs, such as the intestine, skeletal muscle, kidney, adipose tissue and the neural system contribute to morbidity and mortality associated with chronic alcohol abuse. Understanding both the common and tissue-specific mechanisms by which ethanol impairs cellular and organ function will lead to the development of rationally designed therapeutic interventions to both prevent and reverse tissue damage and disease resulting from chronic alcohol consumption. The overall goal of the Northeast Ohio Alcohol Center (NOAC) is to identify specific molecular targets of ethanol-induced damage, as well as understand the complex adaptive and maladaptive responses of cells and systems to that damage, This information will enable us to 1) target therapeutic interventions that will either slow and/or reverse the progression of alcohol-induced organ injury and 2) development of specific assays that can assess the efficacy of novel therapeutic strategies in relevant clinical populations. NOAC brings together an outstanding team of interdisciplinary investigators and is supported by an Administrative Core, an Animal Models and Cell Isolation Core, a Clinical Core and a Pilot Projects Core, as well as outstanding state-of-the-art facilities at 4 premier research institution in Northeast Ohio: the Cleveland Clinic, Case Western Reserve University/University Hospitals, Northeast Ohio Medical University and Nationwide Children's Hospital at the Ohio State University. Four Research Components (RC) are proposed: RC1 (Brown) investigates the interaction between ethanol and gut microbial metabolites and the generation of ethanol-induced tissue injury, RC2 (You) interrogates the impact of ethanol metabolism in liver on lipin-1 and SIRT1, key regulators of hepatocyte lipid homeostasis; RC3 (Dasarathy) is designed to understand the impact of chronic ethanol on skeletal muscle wasting, a critical co-morbid feature of alcoholic liver disease and RC4 (Nagy) investigates the interactions between inflammation and hepatocellular death via necroptosis/apoptosis. The long-term goal of NOAC is to translate novel findings on the specific mechanisms by which ethanol disrupts cellular and organ function into effective treatment strategies for patients with alcoholic tissue injury. Our outstanding investigative team and excellent Core facilities will continue to work collaboratively to address key mechanistic and translational problems of alcohol- induced tissue injury, providing unique strengths for translating novel findings the molecular and cellular mechanisms of ethanol action and disease progression into the development of treatment strategies.